The research team analyzed CD4-cell gene expression data from a study of HIV-infected people in Africa and Asia.
Researchers at the University of North Carolina (UNC) School of Medicine discovered that when HIV infects immune cells called CD4 T cells, it helps fuel its own replication by boosting a key process in the cells’ production of chemical energy. Additionally, they found that the diabetes drug metformin inhibits the same process and thereby suppresses HIV replication in these cells, in both cell-culture and mouse experiments.
“These findings suggest that metformin and other drugs that reduce T cell metabolism might be useful as adjunct therapies for treating HIV,” said study co-first author Haitao Guo, PhD, assistant professor in the UNC Department of Genetics at the UNC School of Medicine, in a press release.
Many patients show signs of residual viral replication and immune impairment despite this treatment, but even patients who respond well to antiretroviral therapy (ART) must take them indefinitely since HIV inscribes itself into the DNA of some infected cells, and the drugs cannot clear this viral genetic reservoir. Further, the toxicity of many anti-HIV drugs means that many patients can take them only intermittently, which leaves a gap in HIV treatment, according to the study authors.
The research team analyzed CD4-cell gene expression data from a study of HIV-infected people in Africa and Asia. They found that the gene-expression patterns most closely related to poor outcomes among these patients involved an energy-production process called oxidative phosphorylation. They found that drugs and other chemical compounds that inhibit oxidative phosphorylation in CD4 cells can inhibit HIV’s ability to replicate in these cells.
Metformin is considered safe and well-tolerated, and the researchers confirmed with further experiments in primary human CD4 cells and in mice with human CD4 cells that metformin suppresses HIV replication in these cells.
The researchers also examined a prior study of patients with HIV taking ART, which showed after 6 months of treatment that patients who had type 2 diabetes had, on average, 33% lower levels of HIV in the blood compared with non-diabetic patients in the cohort. The diabetic patients also had higher baseline CD4 cell levels and quicker recoveries of these levels with ART.
The team traced HIV’s ability to increase oxidative phosphorylation in CD4 cells to its boosting of the levels of NLRX1, a protein associated with the mitochondria. NLRX1 appears to be a key metabolic switch that HIV uses to enhance its replication in CD4 cells, which in turn makes it a potential target for future HIV treatments, according to the study.
“This work shows the importance of CD4 cell metabolism in HIV, and suggests that it may be targetable, for example with repurposed drugs such as metformin, to reduce HIV viral load and restore these disease-fighting CD4 cells,” said co-senior author Jenny Ting, PhD, in a press release.
The researchers plan to continue preclinical studies of metformin’s potential as an anti-HIV treatment or as a therapy that could reduce the need for toxic antiretrovirals that could be given to patients earlier to reduce HIV reservoir formation.
Diabetes drug may be a new weapon against HIV. UNC School of Medicine. Published March 29, 2021. Accessed March 31, 2021. https://news.unchealthcare.org/2021/03/diabetes-drug-may-be-a-new-weapon-against-hiv/